Women 65 and older ("older women") account for nearly half of all new cases of breast cancer. With the "graying of America" the absolute number of older women diagnosed and undergoing breast cancer treatment will almost double by the year 2030. Treatment guidelines for these older patients include systemic therapy and older women are interested in chemotherapy for even small returns in survival extension. But systemic therapy is not without side effects, and numerous studies have documented cognitive decline after receipt of these agents. Imaging and animal studies confirm that cancer chemotherapy affects brain structure and function. However, very little is actually known about cognitive decline in older patients, because virtually all of the existing research has been conducted in younger patients. Since aging itself is associated with cognitive decline, older patients are likely to be particularly vulnerable to the adverse cognitive effects of systemic therapy. Our preliminary work suggests that this is the case, but this has never been empirically tested. This study will be the first large scale, prospective, controlled investigation to evaluate cognitive changes in older cancer patients. We use the vulnerability model of cancer survivorship to describe systemic therapy effects on cognition over a 12 month period, test associations between cognition and quality of life and to evaluate whether APOE polymorphisms moderate cognitive outcomes. We have assembled a team of oncologists, geriatricians, neurologists, neuro-, cognitive and behavioral psychologists and consumers from Lombardi Comprehensive Cancer Center, Memorial Sloan-Kettering Cancer Center, Boston University and Y- Me (a national consumer advocacy organization). We will enroll 325 newly diagnosed older breast cancer patients and an equal number of non-cancer friend controls. Participants will undergo baseline (pre-systemic therapy) neuropsychological testing and telephone interviews;clinical data will be abstracted from records. Participants will repeat cognitive testing and QOL measures 12 months after baseline. The primary outcome is change in the summary score on tests in the Attention, Working Memory, and Psychomotor Speed Domain. Four additional domains are included as secondary outcomes to assess broader cognitive function and examine differential impact: Language;Executive Functioning;Learning and Memory;Visuospatial. The results of this study will contribute to designing appropriate regimens for older women, developing preventive interventions, informing clinical decision-making about treatment, and guiding second generation studies. Overall, this topic has high research, clinical and public health importance, given the projected growth in the older population, rising incidence with advancing age, trends towards increasing use of systemic therapy in older patients, use of more aggressive dosing regimens, high survival rates, and increasing life expectancy. PUBLIC HEALTH RELEVANCE: Cancer is the leading cause of death in the US and breast cancer is the second most common cancer among women in our country. Older women (women 65 and older) presently account for nearly half of all new cases of breast cancer. With the "graying of America" and advances in treatment for breast cancer, the absolute number of older women undergoing breast cancer treatment and surviving their disease will almost double by the year 2030. Systemic hormonal and non-hormonal chemotherapy is credited with improvements in survival, and rates of use of these modalities have increased substantially over the past two decades. In our preliminary work, we have found that older women are interested in chemotherapy even for small returns in survival extension. However, cognitive impairment has been demonstrated in most studies of breast cancer systemic treatments, but virtually all of this research has been conducted in younger populations. Since aging itself is associated with cognitive declines, it seems very likely that older women are particularly vulnerable to the adverse cognitive effects of systemic therapy;our preliminary work strongly suggests that this is the case, but this has never been empirically tested. This study will be the first large scale, prospective, controlled investigation to evaluate cognitive changes in older cancer patients and it will provide the basis for the next generation of mechanistic, treatment and intervention studies. These will be important since data from younger patients cannot be directly translated into the older population. We will use the vulnerability model of cancer survivorship to prospectively describe systemic therapy effects on cognition in older breast cancer patients over a 12 month period, test associations between cognition and quality of life (QOL) and to evaluate whether polymorphisms in the APOE gene moderate cognitive outcomes. To achieve our objectives, we have assembled a multi-disciplinary team of oncologists, geriatricians, neurologists, neuro- and cognitive psychologists, behavioral scientists and consumers from Lombardi Comprehensive Cancer Center (LCCC), Memorial Sloan-Kettering Cancer Center (MSKCC), Boston University (BU) and Y-Me (a national consumer advocacy organization). This team will work together to prospectively enroll 325 newly diagnosed older breast cancer cases from LCCC and MSKCC, tertiary referral centers with high volumes. BU will coordinate cognitive testing protocols. We will recruit an equal number of non-cancer friend controls. We have chosen friend controls since they will be similar to patients in most ways except for exposure to cancer and its treatments and they should be motivated to participate. If friends are not available, we will recruit controls matched to cases on age, education, race, and area (DC/NY). We will administer baseline neuropsychological testing prior to any systemic treatment (or at enrollment for controls), survey women about subjective cognitive function, psychosocial factors, QOL and activities of daily living (IADLS). We will abstract clinical data from medical records. We will obtain blood to test for APOE polymorphisms at enrollment;these results will not be provided to participants since this is considered a research test). We conduct follow-up interviews and repeat the neuropsychological testing 12 months after baseline assessment;this time point corresponds to 3-6 months post-treatment among women who receive chemotherapy. Our primary cognitive outcome will be change in summary score on tests in the Attention, Working Memory, and Psychomotor Speed Domain. In secondary analyses we examine changes in scores on 4 additional domains to assess broader cognitive function and examine questions of differential impact: Language;Executive Functioning;Learning and Memory;Visual-spatial. Data from this study will guide future interventions to better select older women for whom the benefits of systemic therapy outweigh the harms and to develop approaches to mitigate negative consequences of systemic treatment when it is indicated, improving the quality of care for the growing population of older breast cancer patients.